A brief history of familial Mediterranean fever

A familial periodic fever syndromes were described and identified in the latter half of the twentieth century, there have been descriptions of periodic fever since antiquity. In this short historical study, these milestones are briefly described starting with Galen and ending with the characterisation of the Mediterranean FeVer (MEFV) gene towards the end of the twentieth century, and the elucidation of the involvement of the inflammasome in Pyrin action in the early years of the current century. Familial Mediterranean fever (FMF) is the most common of the periodic fever syndromes. It is an inherited polyserositis that mainly affects Arabs, Armenians, Jews, and Turks. It is characterized by recurrent attacks of fever associated with joint, chest, and abdominal pain, and the appearance of an erysipeloid rash lasting 1-3 days. Treatment with colchicine is effective in preventing attacks and reducing the incidence of long-term complications such as amyloidosis. Although familial periodic fever syndromes were only described in detail and identified as discrete entities after the second half of the twentieth century, there have been descriptions of periodic fevers since antiquity. Galen, for instance, described cyclic fevers that he attributed to the different moon phases as early as the second century AD.1 However, description of the various symptoms and organ involvement appeared only in the literature over the past 200 years, where several prominent authors described a syndrome of recurrent attacks of fever, abdominal, and chest pain associated with joint symptoms as shall be described in the following paragraphs. In the book published a year after his death entitled “Commentaries on the history and cure of diseases’’, Heberden wrote in 1802 “besides the pain, which are constantly felt, or rage at certain times, there are others which are regularly intermittent, the fits of which return periodically as those of an ague; such as I have known in the bowels, stomach, breasts, loins, arms, hips, though it be, but seldom that such parts suffer in days and recur for years at remarkably regular short intervals. At that time periodic such a manner”.2 Almost a century later, Osler in 18952 described 11 cases, which periodically presented with different visceral manifestations and various rashes. Five of those cases had joint pain. Some of those cases may well have been auto inflammatory in nature. In addition, Janeway & Mosenthal4 in 1908 reported a young girl with intermittent fever and abdominal pain. The case was reported as “an unsolved diagnostic problem’’.4 Whether these descriptions refer to Familial Mediterranean Fever (FMF) per se, or some other familial periodic fever syndrome is not certain. It is likely that they refer to FMF, since it is the most common of all the periodic fever syndromes. In the case described by Janeway and Mosethal,4 the short duration of fever perhaps points to FMF instead of any other autoinflammatory syndrome. The first accurate description of FMF was published in 1945 by Siegal5 who reported 10 cases of what he described as “at present little understood and often undiagnosed’’ under the name ‘benign paroxysmal peritonitis’. The syndrome since then, appeared under several other names including, periodic peritonitis, familial recurring polyserositis, Cattan-Mamou disease, Siegal-Cattan-Namou syndrome, and periodic disease. The latter term was coined by Reimann6 in 1948, who wrote “In naming them the adjectives periodic, cyclic, rhythmic, episodic, relapsing, paroxysmal, recurrent and intermittent are used interchangeably before the noun indicating the outstanding characteristic, as noted in the title and in the references”.6 Many other names appeared in the literature, including paroxysmal syndrome, Armenian disease, Periodic abdominalgia, La maladie périodique, La maladie dite périodique, La maladie de Siegal-Cattan-Mamou, La maladie périodique de Reimann, Periodic fever, Epanalepsie Mediterranéene and Recurrent polyserositis.7 In 1951, 2 French physicians, Cattan & Mamou, noticed the association of FMF with renal disease.8 The occurrence of amyloidosis was reported 7 years later by Tuqan at the American University of Beirut in Lebanon.9 The actual modern name “familial Mediterranean fever” was coined by Heller et al10 in 1958, who emphasized the genetic nature of the disease. The exact etiology of the disease was unknown for a long time. However, the increased frequency in Arabs, Armenians, Jews, and Turks, and possible hereditary nature was noticed earlier.11 It was not until 1997 that the gene causing FMF (MEFV gene) was finally identified by positional cloning by 2 separate groups, American and French, and was mapped to chromosome 16.12,13 The gene product, a 781 amino acid protein, was named pyrin Brief Report